Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations. We here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6. Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases. Our data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1.

中文翻译：

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功能筛选揭示了非典型畸胎样横纹肌样瘤的遗传依赖性和不同的细胞周期控制


非典型畸胎样横纹肌样瘤 （ATRT） 是无法治愈的高级别小儿脑肿瘤。尽管进行了大量的研究工作，但在目前制定的治疗方案下，ATRT 患者的预后很差。虽然迫切需要新的治疗策略，但分子驱动的治疗概念的产生是一个挑战，主要是因为缺乏可操作的基因改变。我们在这里使用功能基因组学方法来识别 ATRT 中的遗传依赖性，使用功能指导的小分子药物库验证选定的命中，并观察 ATRT 细胞中无亚组特异性选择性的优先活性。CDK4/6 抑制剂是最有效的药物之一，由于相互排斥依赖 CDK4 或 CDK6，因此显示出抗肿瘤功效。化学遗传学相互作用子筛选揭示了广泛的 G1 期细胞周期调节因子，这些调节因子可差异地促进细胞周期进程并调节 ATRT 细胞对 CDK4/6 抑制的反应。在这方面，我们发现泛素连接酶底物受体 AMBRA1 通过调节有丝分裂的关键成分（包括极光激酶）作为细胞周期进程的环境特异性抑制剂。我们的数据提供了 ATRT 中遗传和化学依赖性的全面资源，这将为针对该肿瘤实体的新型靶向治疗的进一步临床前评估提供信息。此外，本研究揭示了细胞周期抑制的独特机制作为 AMBRA1 肿瘤抑制功能的基础。